PROJECT SUMMARY/ABSTRACT The overall long-term objective of this project is to understand the role of the microbiome and host genetics in substance use disorders (SUD). SUD presents a significant and ongoing public health burden in our nation. In 2015, an estimated 20.8 million Americans aged 12 or older had alcohol or other drug use disorders, while approximately 27.1 million people reported past-month illicit drug use. SUD are highly heritable. Indeed, a number of genes have been identified as associated with addiction using candidate gene approaches and GWAS approaches. However, genes identified so far only account for a small proportion of the genetic variants. Accumulating evidence suggests that the gut microbiome plays a significant role in behavioral response to cocaine, as well as anxiety- and depression-like behaviors, many of which are comorbid with addiction. Our preliminary data demonstrates that there is a relationship between the microbiome and addictive behavior. Host genetics can influence the composition of the gut microbiome. The heritability of the gut microbiome is evident from both animal and human studies. In this proposed study, we aim to reveal an integrated genetic basis of addiction that combines host genetics and the microbiome. To achieve this goal, we will leverage our expertise in mouse behavioral genetics, the gut microbiome and also leverage an ongoing project with a collection of Diversity Outbred (DO) samples and phenotyping data to test our hypothesis that the interplay of host genetics and the gut microbiome drives drug addiction. In Specific Aim 1, we will identify genetic loci that control the abundance gut microbiome and overlapping loci between the gut microbiome and novelty related behaviors. In Specific Aim 2, we will identify genetic loci that control addiction in the setting of cocaine exposure using the intravenous drug self-administration (IVSA) system, and also identify overlapping loci between the microbiome and IVSA behaviors. The association of abundance of the microbiome with novelty related behaviors in Aim 1 and IVSA behaviors in Aim 2 will also be determined. In Specific Aim 3, we will construct the gene expression network in the brain and gut, and integrate the network with the microbiome members and metabolic pathways at transcription level. Altogether, our proposed project will be the first to delineate the genetic basis of drug addiction by integrating host genetics and the gut microbiome. If our hypothesis is confirmed, it is likely to lead to the discovery of a novel mechanism of drug addiction and provide novel therapeutic targets for addiction.